Brain-derived HMGB1 mediates periodontal inflammation after ischemic stroke through the STAT3/NLRP3 inflammasome pathway.

Ischemic stroke is known to cause immunosuppression and may exacerbate peripheral conditions such as periodontitis, yet its direct impact on periodontal tissues remains unclear. Using a transient middle cerebral artery occlusion (MCAO) mouse model, we showed that stroke rapidly induced periodontal inflammation, including epithelial disruption, alveolar bone loss, increased osteoclasts, and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Meanwhile, we found that neuronal high-mobility group box 1 (HMGB1) translocated from the nucleus and was released after stroke, coinciding with disruption of the blood-brain barrier and elevated circulating HMGB1. Fluorescent tracing with intracerebroventricular 5-FAM-HMGB1, together with longitudinal periodontal fluorescence quantification and ELISA of gingival tissue (total HMGB1 and 5-FAM-HMGB1), demonstrated that brain-derived HMGB1 contributed to the periodontal HMGB1 pool after MCAO. In parallel, stroke increased hypothalamic HMGB1 and activated the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by increased corticotropin-releasing hormone (CRH) and elevated serum adrenocorticotropic hormone (ACTH) and corticosterone. In addition, recombinant HMGB1 induced inflammatory responses in gingival fibroblasts via signal transducer and activator of transcription 3 (STAT3) signaling. Treatment with the HMGB1 inhibitor Glycyrrhizin (Gly) suppressed brain and hypothalamic HMGB1, inhibited HPA axis hyperactivation, reduced STAT3 phosphorylation and NLRP3 signaling, and attenuated periodontal inflammation; these effects were partially reversed by the STAT3 activator Colivelin. These findings revealed that brain-derived HMGB1 mediated post-stroke periodontal inflammation through both direct migration and HPA axis activation, and highlighted HMGB1 as a critical link in brain-oral crosstalk and a potential therapeutic target.